A1 Adenosine Receptor Antagonists, Agonists, and Allosteric Enhancers

Kiesman, William F.; Elzein, Elfatih; Zablocki, Jeff

doi:10.1007/978-3-540-89615-9_2

Cited by 87 publications

(93 citation statements)

References 76 publications

(74 reference statements)

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“…Another important point is the relatively fast desensitization of Ado receptors [342], which argues for the use or partial agonists in in vivo experiments. The pharmacology of the A 1 receptor has recently been reviewed [343]. Most A 1 receptor agonists are N 6 -substituted Ado derivatives (e.g., selodenoson) (Fig.…”

Section: Recently Developed Drugs Acting On the Adenosinergic System mentioning

confidence: 99%

The Antiepileptic Potential of Nucleosides

Kovács¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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Despite newly developed antiepileptic drugs to suppress epileptic symptoms, approximately one third of patients remain drug refractory. Consequently, there is an urgent need to develop more effective therapeutic approaches to treat epilepsy. A great deal of evidence suggests that endogenous nucleosides, such as adenosine (Ado), guanosine (Guo), inosine (Ino) and uridine (Urd), participate in the regulation of pathomechanisms of epilepsy. Adenosine and its analogues, together with non-adenosine (non-Ado) nucleosides (e.g., Guo, Ino and Urd), have shown antiseizure activity. Adenosine kinase (ADK) inhibitors, Ado uptake inhibitors and Ado-releasing implants also have beneficial effects on epileptic seizures. These results suggest that nucleosides and their analogues, in addition to other modulators of the nucleoside system, could provide a new opportunity for the treatment of different types of epilepsies. Therefore, the aim of this review article is to summarize our present knowledge about the nucleoside system as a promising target in the treatment of epilepsy.

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Section: Recently Developed Drugs Acting On the Adenosinergic System mentioning

confidence: 99%

The Antiepileptic Potential of Nucleosides

Kovács¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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“…2) [27,28]. Capadenoson is a partial A1 receptor agonist with an EC 50 of 0.1 nM on human A1 receptors and a selectivity factor of 1,800 vs. A2a, 900 vs. A2b, and no activity on A3 receptors.…”

Section: Introductionmentioning

confidence: 99%

Partial adenosine A1 receptor agonists for cardiovascular therapies

Albrecht-Küpper

Leineweber

Nell

2011

Purinergic Signalling

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Adenosine, a purine nucleoside, is present in all cells in tightly regulated concentrations. It has many different physiological effects in the whole body and in the heart. Adenosine activates four G protein-coupled receptors A1, A2a, A2b, and A3. Activation of myocardial A1 receptors has been shown to inhibit a variety of myocardial pathologies associated with ischemia and reperfusion injury, including stunning, arrhythmogenesis, coronary and ventricular dysfunction, acute myocardial infarction, apoptosis, and chronic heart failure, implying several options for new cardiovascular therapies for diseases, like angina pectoris, control of cardiac rhythm, ischemic injury during an acute coronary syndrome, or heart failure. However, the main issue of using full A1 receptor agonists in such indications is the broad physiologic spectrum of cardiac and extracardiac effects. Desired A1 receptor-mediated protective and regenerative cardiovascular effects might be counter-regulated by unintended side effects when considering full A1 receptor agonists. These effects can be overcome by partial A1 agonists. Partial A1 agonists can be used to trigger only some of the physiological responses of receptor activation depending on endogenous adenosine levels and on receptor reserve in different tissues. CV-Therapeutics reported the identification of a partial A1 receptor agonist CVT-3619, and recently, another partial A1 receptor agonist VCP28 was published. Both compounds are adenosine derivatives. Adenosine-like A1 receptor agonists often have the drawback of a short half-life and low bioavailability, making them not suitable for chronic oral therapy. We identified the first non-adenosine-like partial A1 receptor agonist(s) with pharmacokinetics optimal for oral once daily treatment and characterized the qualities of the partial character of the A1 receptor agonist(s) in preclinical and clinical studies.

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“…The potential side effects of selective A 1 AR agonists may be mitigated by the use of A 1 AR-selective allosteric enhancers (5,26). Allosteric enhancers for A 1 ARs bind to a site on the receptor that is distinct from the adenosine-binding site (known as the orthosteric site) (5,7).…”

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confidence: 99%